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5-Fluorouracil (5-FU) is a widely used chemotherapeutic agent for breast cancer. However, acquired chemoresistance leads to a loss of its efficacy; methods to reverse are urgently needed. Some studies have shown that pyrotinib, an ErbB receptor tyrosine kinase inhibitor, is effective against HER2+ breast cancer. However, whether pyrotinib sensitizes 5-FU-resistant breast cancer cells to 5-FU is unknown. We hypothesized that the combination of pyrotinib and 5-FU would show synergistic antitumor activity, and pyrotinib could reverse 5-FU resistance in HER2+ breast cancer cells in vitro and in vivo. Our data showed that pyrotinib inhibited the growth of 5-FU-resistant SKBR-3/FU and MDA-MB-453/FU cell lines and the parental cell lines. 5-FU remarkably suppressed the growth of SKBR-3 and MAD-MB-453 cells. However, SKBR-3/FU and MAD-MB-453/FU cells showed resistance to 5-FU. A combination of pyrotinib and 5-FU resulted in the synergistic inhibition of the growth of the 5-FU-resistant SKBR-3/FU and MDA-MB-453/FU cell lines and the parental cell lines. Pyrotinib decreased significantly the IC50 values of 5-FU and the thymidylate synthase (TS) mRNA expression levels in the 5-FU-resistant SKBR-3/FU and MDA-MB-453/FU cell lines and the parental cell lines and increased significantly the intracellular concentration of 5-FU in SKBR-3/FU and MDA-MB-453/FU cells. In addition, pyrotinib reduced the ABCG2 mRNA and protein expression levels in SKBR-3/FU and MDA-MB-453/FU cells and downregulated the protein expression levels of pAKT, pHER2, and pHER4 in all four cell lines. After TS or ABCG2 in 5-FU-resistant breast cancer cells was knocked down, the sensitivity of SKBR-3/FU and MDA-MB-453/FU cells to 5-FU was restored. Moreover, in vivo experiments demonstrated that pyrotinib in combination with 5-FU more effectively inhibited SKBR-3/FU tumor growth than either pyrotinib or 5-FU alone. In conclusion, our findings suggest that pyrotinib could restore sensitivity of 5-FU-resistant HER2+ breast cancer cells to 5-FU through downregulating the expression levels of TS and ABCG2.

Background Human immunodeficiency virus (HIV)-negative plasmablastic lymphoma (PBL) is a rare entity of diffuse large B-cell lymphoma (DLBCL). The clinicopathological features of and optimal treatment for HIV-negative PBL remain largely unknown. Methods To gain insight into this distinct lymphoma, we summarized the clinicopathologic characteristics of 8 unpublished HIV-negative PBLs and performed a comprehensive review of 394 published cases. Results Of the 8 unpublished PBLs, the median patient age was 53.0 years. Four patients presented with stage IV disease. All 8 patients showed a plasma cell-like immunophenotype. Of the six patients who received anthracycline-based chemotherapy, including two who received bortezomib, three patients achieved a continuous complete response, two patients died due to disease progression, and one patient was lost to follow-up. The other two patients achieved continuous complete response after receiving chemotherapy combined with radiotherapy and surgery. Of the 402 patients, the majority were male, with a mean age of 58.0 years. EBV infection was detected in 55.7% of the patients. The median survival times of the patients who received CHOP or CHOP-like regimens and intensive regimens were not reached and 23.0 months, respectively, and the intensive regimen did not improve the survival outcome (P=0.981). Multivariate analysis showed that EBER remained the only independent factor affecting overall survival (OS). Conclusion HIV-negative PBL is a distinct entity with a predilection for elderly and immunosuppressed individuals. Intensive chemotherapy had no apparent survival benefits over the CHOP regimen in terms of OS; the prognosis of this disease is poor with current chemotherapy methods, and treatment remains a challenge.

Background Primary lymphoma of the breast is rare, and primary diffuse large B cell lymphoma (DLBCL) of the breast is very rare. This study aimed to identify the clinicopathological characteristics and treatment associated with prognosis in patients with primary DLBCL of the breast. Material/Methods A retrospective study included the clinical and treatment data from 46 women with a histological diagnosis of primary DLBCL. Patients were staged using Ann Arbor staging criteria, overall survival (OS), progression-free survival (PFS), and the international prognostic index (IPI) scores were obtained. Laboratory finding included serum lactate dehydrogenase (LDH), and the immunohistochemistry findings were recorded. Results Patients (n=46), included stage I (n=18), stage II (n=18), stage III (n=3), and stage IV DLBCL (n=9). Treatment included chemotherapy with rituximab (n=16), and radiotherapy (n=12). The median follow-up time was 40.5 months, the 5-year OS rate was 36.2%, and the 5-year PFS rate was 29.1%. Univariate analysis showed that clinical stage, serum LDH, the IPI score, chemotherapy cycles >3, and Bcl-2 and Bcl-6 expression were correlated with the 5-year OS and PFS. Multivariate risk regression analysis showed that the number of chemotherapy cycles (>3) and Bcl-6 expression were independent prognostic factors in primary DLBCL of the breast (P3 cycles of chemotherapy and expression of Bcl-6 resulted in improved OS and PFS. Radiotherapy controlled local tumor recurrence but did not improve the OS and PFS. Rituximab did not improve patient survival.

Background: Primary thyroid diffuse large B cell lymphoma (DLBCL) is a rare type of extranodal lymphoma; optimal treatment methods and the key prognostic factors have not been established.Methods: The clinical data of 58 patients with primary thyroid DLBCL from January 2007 to December 2017 were collected. The Kaplan–Meier method and log-rank tests were used for the survival analysis. Cox regression analysis was performed to evaluate the prognostic factors.Results: The follow-up time was 6–120 months; 5-year overall survival (OS) and progression-free survival (PFS) were 73 and 61%, respectively. Single-factor analysis showed that IPI, Ki-67, treatment modalities, Hans classification, Myc/Bcl-2 protein co-expression, and administration of rituximab had a significant effect on the 5-year OS and PFS (P < 0.05), while age, sex, Bcl-2 protein expression, Myc protein expression, tumor stage, tumor size, Hashimoto's thyroiditis, and B symptoms were not associated with prognosis (P > 0.05). Multivariate risk regression analysis revealed that Myc/Bcl-2 protein co-expression, treatment modalities, and rituximab were independent prognostic factors (P < 0.05).Conclusions: Patients with primary thyroid DLBCL who received combination chemotherapy with radiotherapy had a better prognosis. Surgical treatment alone was not associated with the prognosis and is used only for diagnosis. Rituximab could improve the survival time of patients.

Rituximab in combination with chemotherapy has shown efficacy in patients with diffuse large B-cell lymphoma (DLBCL) for more than 15 years. HLX01 was developed as the rituximab biosimilar following a stepwise approach to demonstrate biosimilarity in analytical, pre-clinical, and clinical investigations to reference rituximab. With demonstrated pharmacokinetic similarity, a phase 3 multi-center, randomized, parallel, double-blind study (HLX01-NHL03) was subsequently conducted to compare efficacy and safety between HLX01 plus cyclophosphamide, doxorubicin, vincristine, and prednisone (H-CHOP) and reference rituximab plus CHOP (R-CHOP) in a total of 407 treatment-naïve, CD20-positive DLBCL patients aged 18–80 years. The primary efficacy endpoint was best overall response rate (ORR) within six cycles of treatment in the per-protocol set (PPS). Secondary endpoints included 1-year efficacy outcomes, safety, and immunogenicity profile. The results showed difference in ORRs [H-CHOP 94.1%; R-CHOP 92.8%] between two treatment groups was 1.4% (95% confidence interval [CI], − 3.59 to 6.32, p = 0.608) which falls within the pre-defined equivalence margin of ± 12%. The safety profile was comparable between the treatment groups, with a similar overall incidence of treatment-emergent adverse events (H-CHOP 99.5%, R-CHOP 99.0%, p = 1.000) and serious adverse events (H-CHOP 34.0%, R-CHOP 32.5%, p = 0.752). This study established bioequivalence in efficacy and safety between HLX01 and reference rituximab. The trial was registered at http://www.chinadrugtrials.org.cn on 26 August 2015 [#CTR20150583].

Background: Chemotherapy and radiotherapy are critical for treating early-stage extranodal natural killer/T-cell lymphoma, nasal type (ENKTL); however, the optimal therapy sequence remains unclear. Therefore, we performed this study to compare the efficacy of L-asparaginase/pegaspargase-based sequential versus sandwich chemoradiotherapy for patients newly diagnosed with stage IE-IIE ENKTL. Methods: Patients were categorized into sequential (N = 111) and sandwich (N = 104) groups. Chemotherapy regimens included GELOX, SMILE, and VLP. The median radiotherapy dose was 55.0 Gy (range, 40.0-63.0 Gy). Adverse events, treatment responses, and survival outcomes were analyzed. Results: Patients' clinical characteristics were largely comparable between the 2 groups; however, the sandwich group comprised a larger number of Ann Arbor stage IIE patients. Local invasion was the most significant predictor of overall survival (OS); local invasion and Ann Arbor stage were significant predictors of progression-free survival (PFS). There were no significant differences in the complete response rate (85.6% vs. 89.4%, p = 0.396), 3-year OS (77.5% vs. 80.8%, p = 0.636), or 3-year PFS rates (74.8% vs. 76.9%, p = 0.806) in the sequential vs. sandwich groups, respectively. The incidence of grade 3/4 hematological toxicities was higher in the sandwich group than in the sequential group (27.9% vs. 15.3%, respectively, p = 0.025). The response rates and survival outcomes in stage IE and IIE patients did not differ between sequential and sandwich groups. Conclusions: In the era of L-asparaginase/pegaspargase, both sequential and sandwich chemoradiotherapy are safe and similarly effective in patients with newly diagnosed stage IE-IIE ENKTL.

The PI3K pathway and epigenetic regulation have been shown to play a pivotal role in the development and progression of diffuse large B-cell lymphoma (DLBCL). In the clinic, existing PI3K and HDAC inhibitors show limited efficacy as single agents toward DLBCL. However, in preclinical studies, the synergistic effects of PI3K inhibitors and HDAC inhibitors on DLBCL have sparked the enthusiasm of researchers to target both PI3K and HDAC. We hypothesized that a novel dual PI3K/HDAC inhibitor, BEBT-908, would display improved pharmacologic effects on DLBCL. We analyzed the anti-DLBCL activity of BEBT-908 in a comprehensive manner, demonstrating its role in the suppression of in vitro cell proliferation, blockade of PI3K and HDAC activities, inhibition of multiple signaling pathways, and promotion of apoptosis and cell cycle arrest. BEBT-908 showed potent PI3K/HDAC inhibition, with nanomolar IC50 values against DLBCL cell lines. Moreover, BEBT-908 inhibited multiple pathways, including JAK/STAT3, MAPK/ERK and NF-κB, and induced apoptosis and cell cycle arrest at G1 phase in these cells. Additionally, dual PI3K/HDAC inhibition was superior to the inhibition of PI3K or HDAC alone. The dual inhibitor BEBT-908 is a promising lead compound for developing novel targeted therapeutic agents against DLBCL.

Objectives Nasal-type extranodal natural killer NK/T-cell lymphoma (ENKTCL) is a distinct type of non-Hodgkin lymphoma with poor prognosis. This research aimed to evaluate the efficacy and safety of the GELOXD or P-GEMOXD regimens in patients with ENKTCL. Methods Newly diagnosed ENKTCL patients treated with either the GELOXD or the P-GEMOXD regimen were identified from three cancer centers between January 2010 and December 2016. Kaplan-Meier and Cox regression analyses were used to calculate overall survival (OS) and progression-free survival (PFS) and to investigate prognostic factors. Results One hundred and eighty-four cases were identified from three cancer centers. After 1-5 treatment cycles of GELOXD or P-GEMOXD chemotherapy, 155 (84%) patients showed a complete response (CR). The 3-year OS (73.0% vs 38.2%, P = .001) and PFS (72.8% vs 32.4%, P = .000) rates were significantly higher in early-stage patients compared with advanced-stage patients. A multivariate analysis revealed that patient CR status was a significant independent factor in disease prognosis. Grade 3/4 leukopenia occurred in 43 (23.4%) patients. Major non-hematological toxicities included nausea (n = 117, 63.6%) and vomiting (n = 66, 35.9%). Conclusions The GELOXD and P-GEMOXD chemotherapy regimens are well tolerated and provide favorable survival outcomes in patients with ENKTCL.

The efficacy and safety of chidamide, a new subtype-selective histone deacetylase (HDAC) inhibitor, have been demonstrated in a pivotal phase II clinical trial, and chidamide has been approved by the China Food and Drug Administration (CFDA) as a treatment for relapsed or refractory peripheral T cell lymphoma (PTCL). This study sought to further evaluate the real-world utilization of chidamide in 383 relapsed or refractory PTCL patients from April 2015 to February 2016 in mainland China. For patients receiving chidamide monotherapy (n = 256), the overall response rate (ORR) and disease control rate (DCR) were 39.06 and 64.45%, respectively. The ORR and DCR were 51.18 and 74.02%, respectively, for patients receiving chidamide combined with chemotherapy (n = 127). For patients receiving chidamide monotherapy and chidamide combined with chemotherapy, the median progression-free survival (PFS) was 129 (95% CI 82 to 194) days for the monotherapy group and 152 (95% CI 93 to 201) days for the combined therapy group (P = 0.3266). Most adverse events (AEs) were of grade 1 to 2. AEs of grade 3 or higher that occurred in ≥5% of patients receiving chidamide monotherapy included thrombocytopenia (10.2%) and neutropenia (6.2%). For patients receiving chidamide combined with chemotherapy, grade 3 to 4 AEs that occurred in ≥5% of patients included thrombocytopenia (18.1%), neutropenia (12.6%), anemia (7.1%), and fatigue (5.5%). This large real-world study demonstrates that chidamide has a favorable efficacy and an acceptable safety profile for refractory and relapsed PTCL patients. Chidamide combined with chemotherapy may be a new treatment choice for refractory and relapsed PTCL patients but requires further investigation. Electronic supplementary material The online version of this article (doi:10.1186/s13045-017-0439-6) contains supplementary material, which is available to authorized users.

7552Background: The survival of patients with extranodal natural killer T-cell lymphoma (ENKTL), a rare and highly aggressive malignancy, is not accurately predicted by the routine lymphoma Ann Arb...

Although there have been substantial advances in our knowledge of the resistance of diffuse large B cell lymphoma (DLBCL) to chemotherapy, there are few efficient treatment strategies for recurrent/refractory DLBCL. The aim of this study was to investigate the role of aldehyde dehydrogenase (ALDH) 1A1 in the resistance of diffuse large B cell lymphoma to the chemotherapeutic mixture consisting of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). The involvement of ALDH1A1 in DLBCL was elucidated by knockdown and pharmacologic inhibition; Cell Counting Kit-8 (CCK-8) and clone formation assays were used to determine its role in CHOP sensitivity and clone formation ability. Caspase colorimetric assay was used to measure the extent of apoptosis. Western blot analysis was used to measure signal transducer and activator of transcription 3 (STAT3)/nuclear factor kappa B (NF-κB) signaling proteins, and quantitative real-time PCR (RT-PCR) was used to measure the differential expression of ALDH1A1 of DLBCL patients and healthy donors. ALDH1A1 showed a 5.64-fold higher expression in malignant B cells than in normal B cells. Diethylaminobenzaldehyde (DEAB) decreased the half maximal inhibitory concentration (IC50) of the CHOP regimen in Farage cells from 344.78 ± 65.75 to 183.88 ± 49.75 ng/ml (P = 0.004). Both knockdown and inhibition of ALDH1A1 reduced clonogenicity, increased caspase-3/caspase-9 activity, and attenuated the phosphorylation status of STAT3/NF-κB. The prognosis of patients with a high level of ALDH1A1 expression was poor compared with that of patients with low levels of expression (P = 0.044). ALDH1A1 is a new mediator for resistance of DLBCL to CHOP; it is a predictor of clinical prognosis and may serve as a potential target to improve chemotherapy responsiveness of human DLBCL.